The present invention relates to polyvinyl alcohol gels, especially hydrogels manufactured using new methods and formulations and having a property profile which can be adjusted over a wide range of excellent mechanical properties.
Polyvinyl alcohol (PVA) which can be obtained by hydrolysis of polyvinyl acetate for example is almost completely biologically degradable and has good water solubility at elevated temperature. PVA-based hydrogels can be manufactured with the consistency of biological tissue and cartilage and exhibit exceptional stability and biocompatibility in the living organism, which is attributable on the one hand to the high water content of these gels and on the other hand to the macromolecule itself which, as a result of the numerous hydroxyl groups similar to water is “perceived as polymerised long-chain water” by the body when pointedly expressed. Thus, PVA gels (PVAG) are almost predestined for applications in the living organism, especially PVAG manufactured without chemical cross-linking, radiation cross-linking and without the aid of problematical chemicals.
In the conventional methods for manufacturing these PVAGs in a first step at elevated temperatures of 120° C., for example, a solution of PVA is prepared and this can be poured into a mould cooled to room temperature. Various methods for gel formation are applied subsequently wherein the PVA solution is frozen at least once and then thawed again (freeze/thaw). Typically, the solvent is water, the PVA solutions have a PVA concentration Cp in the range of 5-15% and are cooled at cooling rates of about 0.1° C./min to temperatures of around −15 to −30° C., left at this temperature for about 1-24 h and then thawed again at about 0.1° C./min. After such a cycle the PVAGs are opaque and very soft. They can already be damaged by touching, the strength sm of a PVAG with Cp=15%, for example, is in the range of 0.04 MPa and the modulus of elasticity E is in the range of 0.01 MPa. The mechanical properties are continually improved by repeating the freeze/thaw treatment, after 10 cycles for example, the strength sm is in the range of 1 MPa and the modulus of elasticity in the range of 0.1 MPa. After further cycles, the mechanical properties are only slightly further improved. Such PVAGs have been described on numerous occasions in the prior art, for example, F. Yokohama et al. in Colloid & Polymer Science (1986), 264, pages 595-601.
A modified method is described in U.S. Pat. No. 4,734,097 wherein, starting from an aqueous PVA solution, e.g. in example 3 with Cp=8% only one freeze/thaw cycle is applied and the PVA-water mixture is dehydrated to a concentration Cp of 42% in the frozen state by using a vacuum for 10 hours. After thawing, a whitish opaque gel having a strength sm of 0.5 MPa is obtained, which was suggested for use as artificial tissue in the human body. Applications to patent PVAG manufactured by this method have been made for numerous applications, for example, for artificial organs and membranes in EP 0107055 (artificial organs or membranes for medical use), as dermal gels in EP 0095892 (wound-covering materials), for use as cooling medium in EP 0070986 (gel for use as cooling-medium), as insulation gel for low temperatures in JP 57190072, as phantoms for NMR diagnosis in GB 2209401 (phantoms for NMR diagnosis) or as golf ball filling in GB 2182571 (golf ball cores).
A further modified method is described in U.S. Pat. No. 6,231,605 wherein, starting from an aqueous PVA solution, e.g. in example 1 with Cp=15% three freeze/thaw cycles were first applied at −20° C. whereafter the gel obtained was placed in water and thus swollen. The gel was transparent in this state but so weak that it could not maintain its shape outside water. The swollen gel was then subjected to another two freeze/thaw treatments and an opaque elastic gel having a modulus of elasticity of around 0.4 MPa was then obtained. Such gels were also proposed for use as tissue replacement in the human body, e.g. for heart valves, vessels, tendons, cartilage, urethral meniscus.
In a further modified method in U.S. Pat. No. 4,663,358 the PVA solution is prepared using mixtures of water and organic solvents, especially DMSO, and then frozen at −20° C. The gel obtained is then stored in water to extract most of the DMSO, dried in the atmosphere and then under vacuum to extract the remainder of the DMSO. After swelling the samples in water, PVAG was obtained which had a transparency of up to 99% and strengths of up to 5.6 MPa. Such transparent PVAG was proposed for applications in the field of biomedicine and for the food industry.
As has been mentioned, said methods for manufacturing biocompatible PVAG have the common feature that they start from a pourable solution and at least one freeze/thaw cycle is applied. It is known to the person skilled in the art that the mechanical properties of the PVAG obtained in the various versions of the method increase with the concentration Cp of the PVA used in the solution, with increasing degree of polymerisation DP and with increasing degree of hydrolysis. In this method, however, the parameters Cp and DP cannot be optimised independently of each other since advantageous higher degrees of polymerisation DP cause the viscosity of the solution to increase substantially so that it becomes difficult to prepare a solution and it is no longer pourable. Maximum solution viscosities lie in the range of 10,000 mPa. For example, Mowiol 66-100, one of the highest-molecular commercially available PVAs with a degree of hydrolysis DH of 99.4% and a degree of polymerisation DP of around 4,500 already has the maximum processable viscosity of 10,000 mPa at a concentration Cp of 10% at room temperature, at 80° C. the limiting concentration Cp is around 15%. In the case of higher-molecular PVA, the limiting concentration is even lower. This is an important disadvantage of the conventional methods. A further disadvantage is the long time required by the conventional methods, a single freeze/thaw cycle for example lasts at least 24 h, dehydration by lyophilisation takes about 10 h, the removal of organic solvents takes days. On the whole it is desirable to be able to process higher concentrations Cp, to develop simpler and shorter methods, to improve the mechanical properties of PVAG (higher strengths and moduli of elasticity) and to achieve transparency even in pure PVA water systems without the assistance of organic solvents which must be 100% removed again, which is barely possible in practice since traces thereof always remain.